Compositions, methods of use and preparation of 2,6-diisopropyl phenol and analogs for ischemic injury

Abstract

The present invention provides novel 2,6-diisopropyl phenol2,6-diisopropyl phenol analogs and sterile, stable pharmaceutical compositions of 2,6-diisopropyl phenol 2,6-diisopropyl phenol and analogs thereof useful as an antioxidant in the treatment of ischemic injury including stroke and other cerebral injury. 2,6-diisopropyl phenol or its analogs are administered in a dosage effective to produce blood levels and brain levels of the drug that can prevent free radical damage associated with ischemic injury.

1. A method of treating or ischemic injury in a human, wherein the method comprises administering to the human an amount of a 2,6-diisopropyl phenol analog selected from the group consisting of: (4-fluorophenyl)-(4-hydroxy-3,5-diisopropylphenyl)methanone, (4-(trifluoromethyl)phenyl)-(4-hydroxy-3,5-diisopropylphenyl)methanone, (4-3,5diisopropylphenyl(4-nitrophenyl)methanone, (3-fluoro-4-(trifluoromethyl)phenyl)-(4-hydroxy-3,5-diisopropylphenyl)methanone, (3-(trifluoromethyl)phenyl)-(4-hydroxy-3,5-diisopropylphenyl)methanone, (3-fluoro-5-(trifluoromethyl) phenyl)-4-hydroxy-3,5-diisopropylphenyl)methanone, (4-hydroxy-3,5-diisopropylphenyl)naphthalene-2-yl)methanone, (3,5-bis(trifluoromethyl)phenyl)-(4-hydroxy-3,5-diisopropylphenyl)methanone, (4-tert-butylphenyl)-(4-hydroxy-3,5-diisopropylphenyl)methanone, (4-hydroxy-3,5-diisopropylphenyl)-(4-isobutylphenyl)methanone, (4-hydroxy-3,5-diisopropylphenyl)-(4-iodophenyl)methanone, (4-hydroxy-3,5-diisopropylphenyl)-(4-methoxyphenyl)methanone, (4-cyanophenyl)-4-hydroxy-3,5-diisopropylphenyl)methanone, (6-(trifluoromethyl)pyridin-3-yl)-(4-hydroxy-3,5-diisopropylphenyl)methanone, (4-bromophenyl)-(4-hydroxy-3,5-diisopropylphenyl)methanone, (4-hydroxy-3,5-diisopropylphenyl)-(4-propylphenyl)methanone, (4-chlorophenyl)-(4-hydroxy-3,5-diisopropylphenyl)methanone, 4-((4-(trifluoromethyl)phenyl)-(methoxyimino)methyl)-2,6-diisopropylphenyl, 4-(4-(trifluoromethyl)benzyl)-2,6-diisopropylphenyl, 4-((4-(trifluoromethyl)phenyl)-(hydroxy)methyl)-2,6-diisopropylphenyl, 4-hydroxy-3,5-diisopropylphenyl)-(4-(methylsulfonyl)phenyl)methanone, and combinations thereof. 
     
     
       2. The method of  claim 1  wherein the 2,6-diisopropyl phenol analog is included in a pharmaceutical composition. 
     
     
       3. The method of  claim 2 , wherein the 2,6-diisopropyl phenol analog is administered by a method selected from the group consisting of oral administration, nasal respiratory administration, aerosol administration, bolus injection, intravenous administration, continuous infusion, intra-arterial administration, rectal administration, vaginal administration, sublingual administration, parenteral administration and cutaneous administration. 
     
     
       4. The method of  claim 3 , wherein the pharmaceutical composition is for parenteral administration. 
     
     
       5. The method of  claim 2 , wherein the pharmaceutical composition comprises nanoparticles of the 2,6-diisopropyl phenol analog. 
     
     
       6. The method of  claim 5 , wherein the pharmaceutical composition is for parenteral administration. 
     
     
       7. The method of  claim 2 , wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier. 
     
     
       8. The method of  claim 1 , wherein the ischemic injury is induced by stroke, hemorrhage or trauma. 
     
     
       9. The method of  claim 1 , wherein the 2,6-diisopropyl phenol analog is 4-(trifluoromethyl)phenyl)-(4-hydroxy-3,5-diisopropylphenyl)methanone. 
     
     
       10. The method of  claim 9 , wherein the composition is administered continuously. 
     
     
       11. The method of  claim 9 , wherein the composition is administered one or more times a day. 
     
     
       12. A method of treating or ischemic injury in a human with a pharmaceutical composition comprising:
 a) 0.5-5 wt % 2,6-diisopropyl phenol or an analog thereof, and 
 b) 0.1-5 wt % oil, 
 wherein, the composition is administered to a human in an amount effective to treat ischemia. 
 
     
     
       13. The method of  claim 12 , wherein the composition further comprises 0.1 to 3 wt % human serum albumin. 
     
     
       14. The method of  claim 12 , wherein the composition further comprises 0.05 to 1 wt % lecithin. 
     
     
       15. The method of  claim 12 , wherein the composition further comprises 0.1 to 2 wt % vitamin E-TPGS. 
     
     
       16. The method of  claim 12 , wherein the composition further comprises about 2.25% glycerol. 
     
     
       17. The method of  claim 12 , wherein the pharmaceutical composition has a pH of about 5 to about 8. 
     
     
       18. A method for treating ischemia in a human comprising administering to a human a low oil composition comprising 2,6-diisopropyl phenol or an analog thereof in an amount effective to treat ischemia. 
     
     
       19. The method of  claim 18 , wherein the composition contains less than 5 wt % oil. 
     
     
       20. The method of  claim 19 , wherein the composition contains less than 3 wt % oil. 
     
     
       21. The method of  claim 20 , wherein the 2,6-diisopropyl phenol analog is 4-(trifluoromethyl)phenyl)-(4-hydroxy-3,5-diisopropylphenyl)methanone. 
     
     
       22. The method of  claim 19 , wherein the analog is selected from the group consisting of:
 (4-fluorophenyl)-(4-hydroxy-3,5-diisopropylphenyl)methanone, 
 (4-(trifluoromethyl)phenyl)-(4-hydroxy-3,5-diisopropylphenyl)methanone, 
 (4-hydroxy-3,5-diisopropylphenyl)-(4-nitrophenyl)methanone, 
 (3-fluoro-4-(trifluoromethyl)phenyl)-(4-hydroxy-3,5-diisopropylphenyl)methanone, 
 (3-(trifluoromethyl)phenyl)-(4-hydroxy-3,5-diisopropylphenyl)methanone, 
 (3-fluoro-5-(trifluoromethyl)phenyl)-(4-hydroxy-3,5-diisopropylphenyl)methanone, 
 (4-hydroxy-3,5-diisopropylphenyl)-(naphthalen-2-yl)methanone, 
 (3,5-bis(trifluoromethyl)phenyl)-(4-hydroxy-3,5-diisopropylphenyl)methanone, 
 (4-tert-butylphenyl)-(4-hydroxy-3,5-diisopropylphenyl)methanone, 
 (4-hydroxy-3,5-diisopropylphenyl)-(4-isobutylphenyl)methanone, 
 (4-hydroxy-3,5-diisopropyIphenyl)-(4-iodophenyl)methanone, 
 (4-hydroxy-3,5-diisopropylphenyl)-(4-methoxyphenyl)methanone, 
 (4-cyanophenyl)-(4-hydroxy-3,5-diisopropylphenyl)methanone, 
 (6-(trifluoromethyl)pyridin-3-yl)-(4-hydroxy-3,5-diisopropylphenyl)methanone, 
 (4-bromophenyl)-(4-hydroxy-3,5-diisopropylphenyl)methanone, 
 (4-hydroxy-3,5-diisopropylphenyl)-(4-propylphenyl)methanone, 
 (4-chlorophenyl)-(4-hydroxy-3,5-diisopropylphenyl)methanone, 
 4-((4-(trifluoromethyl)phenyl)-(methoxyimino)methyl)-2,6-diisopropylphenol, 
 4-(4-(trifluoromethyl)benzyl)-2,6-diisopropylphenol, 
 4-((4-(trifluoromethyl)phenyl)-(hydroxy)methyl)-2,6-diisopropylphenol, 
 4-hydroxy-3,5-diisopropylphenyl)-(4-(methylsulfonyl)phenyl)methanone, and combinations thereof. 
 
     
     
       23. The method of  claim 18 , wherein the composition contains less than 2 wt % oil.